Cytokines & Cells Online Pathfinder Encyclopaedia
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A mechanism of growth control involving the direct action of cytokines within a cell.
It has been observed that some factors, including bFGF, EGF, NGF and PDGF, produce factor/receptor complexes that are rapidly internalized by the cells and translocated to the nucleus without being degraded. In addition, the activity of some growth factors cannot be inhibited completely by antibodies directed against these factors (see also: UTMC-2 cells).
An intracrine mechanism of growth control would create an internal autocrine loop requiring the presence of suitable intracellular biologically active receptors. The mechanisms underlying intracrine growth control are largely unknown. They might involve direct modulation of DNA replication and/or transcription (see also: gene expression) in response to growth factor/receptor complexes reacging the nucleus.
Since some cytokines, including aFGF, bFGF, CNTF and PD-ECGF do not possess a secretory signal sequence allowing their release by classical secretory pathways via the endoplasmic reticulum/Golgi system an intracrine activity could be a further mechanism explaining at least some of their biological actions.
It has been demonstrated that bFGF contains a nuclear transport sequence (abbr. NTS) in its aminoterminal sequence (see also: signal sequence) that mediates the transport of this factor into the nucleus. Deletion of this targeting sequence generates a variant of bFGF that is no longer mitogenic but retains all other activities normally elicited after binding of this factor to its receptor, including tyrosine phosphorylation (see also: PTK; protein tyrosine kinase) and induction of early gene synthesis.
Wiley et al (1998) have described experiments in which genes encoding modified forms of EGF from which the membrane-anchoring domain had been removed are expressed in human mammary epithelial cells. In these cells EGF colocalizes with the EGF receptor within small cytoplasmic vesicles. Proliferation rate, growth at clonal densities, and receptor substrate phosphorylation are not affected by antibodies directed against the EGF receptor which seems to suggest the existence of an intracrine signaling pathway.
The ability to be secreted via the classical secretory pathway involving the use of signal sequences and interaction with cell surface receptors does not preclude the ability to enter the nucleus directly following translation and influence cellular events in an intracrine fashion.
Lin et al (1997) have reported that the hepatocellular carcinoma cell lines HuH-7 and HepG2 produce larger amounts of intracellular IGF-2 than other cell lines and that suppression of IGF-2 production by suitable antisense oligonucleotides causes a decrease in cell proliferation. The use of the antisense oligonucleotides in other cell lines that produce lower levels of IGF-2 had no effect.
Re (2004) has suggested that intracrine expression/action may cause long-lived intra- and intercellular intracrine feedback loop networks, which can affect cellular ion flows over short time periods and stimulate protein synthesis and growth over longer periods. In the cerebral cortex they might participate in producing both short- and long-term synaptic potentiation, which can integrate information and ultimately result in the formation of the associations that underlay consciousness.
For other mechanisms of growth control see also: autocrine, juxtacrine, paracrine, retrocrine, trans-signaling. For strategies used to exploit intracrine modulation of growth factor activities see also: antisense RNA.
LAST MODIFIED: February 2004
See REFERENCES for entry Intracrine
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